This invention relates to the enhancement of the biocompatibility of various surfaces by binding biomolecules containing carboxyl groups to aminated surfaces.
Medical devices which serve as substitute blood vessels, synthetic and intraocular lenses, electrodes, catheters and the like in and on the body or as extracorporeal devices intended to be connected to the body to assist in surgery or dialysis are well known. However, the use of such biomaterials in medical devices can stimulate adverse body responses, including rapid thrombogenic action. Various plasma proteins play a role in initiating platelet and fibrin deposition on plastic surfaces. These actions lead to vascular constriction to hinder blood flow, and the inflammatory reaction that follows can lead to the loss of function of the medical device.
A "biomaterial" may be defined as a material that is substantially insoluble in body fluids and that is designed and constructed to be placed in or onto the body or to contact fluid of the body. Ideally, a biomaterial will not induce undesirable reactions in the body such as blood clotting, tissue death, tumor formation, allergic reaction, foreign body reaction (rejection) or inflammatory reaction; will have the physical properties such as strength, elasticity, permeability and flexibility required to function for the intended purpose; can be purified, fabricated and sterilized easily; will substantially maintain its physical properties and function during the time that it remains implanted in or in contact with the body
As used herein, the solid surface of a biomaterial is characterized as "biocompatible" if it is capable of functioning or existing in contact with biological fluid and/or tissue of a living organism with a net beneficial effect on the living organism. Long term biocompatibility is desired for the purpose of reducing disturbance of the host organism. One approach to improved biocompatibility for biomaterials is to attach various "biomolecules" such as growth factors, antimicrobial agents, antithrombogenic agents, and cell attachment proteins to the surface of the material.
A number of approaches have been suggested to attach such biomolecules. One such approach is set forth in U.S. Pat. No. 4,521,564 to Solomon et al. in which an antithrombogenic agent is bonded to a solid polyurethane polymer support. A polymeric amine such as polyvinyl amine, or a polyalkyleneamine is first covalently bonded to the polyurethane substrate to provide an aminated surface. Then, an antithrombogenic agent is covalently bonded to the aminated substrate. The antithrombogenic agent is covalently bonded by first activating the antithrombogenic agent with a carbodiimide and then reacting it with the aminated surface of the substrate material. However, in Funahashi et al. "Preparation of Three Types of Heparin-Sepharose and Their Binding Activities to Thrombin and Antithrombin III" Analytical Biochemistry 126, 414-421 (1982), it was noted that by using the carbodiimide to bind an antithrombogenic agent (e.g. heparin) for an affinity chromatography support, that the carboxyl groups which provide the biomolecule with much of its bioactivity had reacted with the carbodiimide, thereby substantially reducing antithrombin III uptake.
It is therefore an object of the present invention to provide a biocompatible surface having active, covalently bonded biomolecules thereon.
It is also an object of the present invention to covalently attach biomolecules having carboxyl groups to aminated surfaces while retaining their bioactivity.
It is also an object of the present invention to preserve the bioactivity of biomolecules attached by the use of a carbodiimide.